Inter alpha inhibitor proteins (IAIPs) are a family of structurally related proteins found in mammalian plasma in relatively high concentrations. IAIPs play important roles in inflammation as part of innate immunity, wound healing, and cancer metastasis (A1-A3). The major forms found in human plasma are inter-alpha inhibitor (IaI), which consists of two heavy chains (H1 and H2) and a single light chain, and pre-alpha inhibitor (PaI), which consists of one heavy (H3) and one light chain. The light chain (bikunin) is known to inhibit several serine proteases, such as trypsin, human leukocyte elastase, plasmin, and cathepsin G (A1, A4). The liver is the major site of synthesis of the heavy and light chains of IAIP (A3, A5). The high levels of circulating IAIPs normally found in plasma of adults and newborns, and even in prematurely born infants, suggest that these proteins are important. Moreover, complete absence of IAIPs has not been reported in humans (A1), suggesting that these proteins have significant functions in human biology. In premature infants, IAIPs have recently been shown to decrease in association with sepsis and necrotizing enterocolitis (NEC) (A6-A8). In addition, both disorders are associated with increased incidences of brain damage in premature infants (A9, A10).
The decreased plasma levels found in septic patients and concomitant increases of IAIP-related fragments in the urine suggest that these proteins are “consumed” and rapidly cleared from the systemic circulation during sepsis (A2, A11, A12). Although the physiological functions of IAIPs remain to be established, current findings suggest that these molecules are part of innate immunity and play a critical role during inflammation. IAIPs have unique immunomodulatory effects by reducing TNF-α during systemic inflammation and augmenting anti-inflammatory IL-10 during sepsis in neonatal rats (A2, A13, A14). The urinary trypsin inhibitor or bikunin has also been suggested to be effective in inhibiting premature delivery most likely by suppressing cytokines and other inflammatory mediators (A15-A19). In addition, recent observations demonstrate that IAIPs attenuate complement activation through the classical and alternative pathways, inhibit complement-dependent phagocytosis in vitro, and reduce complement-dependent lung injury in vivo (A20). These functions potentially provide mechanistic explanations for its beneficial effects in systemic inflammation and sepsis and suggest that IAIPs could play an important role in inflammation-related disorders during the perinatal period.
The function of the choroid plexus (CP) and its product cerebral spinal fluid (CSF) has been thought of as providing physical protection to the brain and facilitating the removal of brain metabolites through the drainage of CSF. However, more recent studies suggest that the choroid plexus-cerebral spinal fluid system plays a much more active role in the development, homeostasis, and repair of the central nervous system (CNS) (A39-A41). CP is a highly specialized tissue, strategically positioned within the ventricles to provide the CNS with a variety of biologically active growth factors that are essential for normal brain development (A40-A42). These factors include a number of neurotrophic and angiogenic factors, such as transforming growth factor-α and -β superfamily, insulin-like growth factor, and vascular endothelial growth factor (VEGF), (43-52) and chemo repellents, such as semaphoring 3f and slit protein (A53, A54) that appear to be involved in neurogenesis and axonal guidance during development of CNS, in response to brain injury, and possibly in the subsequent repair processes. Previous studies reported that during development in many species including human premature infants, cerebral spinal fluid has very high protein concentrations, which are most likely important for brain development (A55-A58). Therefore, proteins found in cerebral spinal fluid most likely influence brain development and responses to injury. Although IAIPs are most likely immunomodulatory compounds, their levels have not been previously reported in CSF in any species during development.
Information is also very limited regarding the distribution of these IAIP molecules among different organs, including brain. In humans, IAIPs were detected in cerebrum, cerebellum, lungs, kidney, liver, colon, skin, and testes (A22). Information is not available regarding the expression of IAIPs in the brain or somatic organs during normal development.
Tissue ischemia, e.g., persistent restriction of blood supply to a tissue, can impair tissue function and result in tissue and organ damage. Tissue ischemia in critical organ systems or body parts, for example, heart, brain, kidneys, skin, limbs, or gastrointestinal tract, contributes significantly to human morbidity and mortality, and thus there is a continuing need for therapeutic strategies for treating or protecting the affected tissues.